As the protein folds: The tail of the gene tells the tale of Machado-Joseph disease

PHILADELPHIA – The repetition of three little "letters" within the gene that codes for the ataxin-3 protein is both the cause of – and perhaps a solution to – Machado-Joseph disease and an entire family of similar genetic disorders, according to researchers at the University of Pennsylvania. Their findings, which appear today in the journal Molecular Cell, present a potential therapeutic role for the ataxin-3 protein for MJD and related disorders such as Huntington's disease.

Machado-Joseph disease is among the most common of the nine known polyglutamine repeat disorders, a family of diseases in which the genetic code for the amino acid polyglutamine – CAG – becomes excessively repeated within the gene, making the protein toxic. In these diseases, the expanded polyglutamine domain causes the errant protein to fold improperly, which causes a glut of misfolded protein to collect in tissues of the nervous system, much like what occurs in Alzheimer's and Parkinson's diseases.

"In origami, if you misfold the paper, you can just throw the paper into the recycling bin," said Nancy Bonini, a Penn professor of biology and Howard Hughes Medical Institute investigator. "If a protein misfolds, cells rely on their own recycling system to dispose of it. It turns out that ataxin-3 may influence this system, especially for recycling those that have misfolded due to excessive polyglutamine repeats. Our findings show that ataxin-3 not only blunts the toxicity of mutant versions of itself but can also mitigate neurodegeneration induced by other such mutant polyglutamine proteins."

Machado-Joseph disease is among the most common dominantly inherited ataxias, a neurodegenerative disorder marked by a gradual decay of muscle control. MJD typically appears in adulthood, with a longer repeat expansion being associated with earlier onset and more severe disease. Its symptoms, uncoordinated motor control, worsen with time.

To study just how the ataxin-3 protein relates to disease, Bonini and her colleagues worked in a simple model organism, the fruit fly, engineering flies to express both the normal human ataxin-3 protein (the protein encoded by the SCA3 gene) and a toxic human disease form of ataxin-3 with an expanded polyglutamine repeat. When both genes are in the same fruit fly, however, the functioning gene helps protect against the effects of the bad one. Their studies surprisingly demonstrated that the protective function of the ataxin-3 protein does not rely on the multiple repeats in its tail but in a region near the head. Indeed, it seems that removing or altering this region of the gene can accelerate the progress of the disease.

"The secret of ataxin-3 is that regions near the start of the protein can counterbalance the toxicity conferred by the excessive polyglutamine repeats in the mutant protein," Bonini said. "In fact, we found evidence that mutant ataxin-3 with the extra-long polyglutamine tail can mitigate its own toxicity."

According to the researchers, it may explain why even normal ataxin-3 can have multiple CAG repeats without causing disease. In other polyglutamine diseases, mutant genes with far fewer repeats can still be toxic, whereas ataxin-3 disease mutations are generally associated with much longer repeats.

"One question now is how this information can be used clinically," Bonini said. "While more research needs to be done, we are hopeful that ataxin-3 may prevent the protein accumulation associated with polyglutamine diseases and perhaps other neurodegenerative situations as well."

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By John M. Grohol, Psy.D. on
21 Feb 2009
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